title: Different pathways of colony-stimulating factor 1 degradation in macrophage populations revealed by wortmannin sensitivity.
abstract: Phosphatidylinositol 3'(OH)-kinase (PI 3-kinase) is activated on stimulation of macrophages with colony-stimulating factor 1 (CSF-1). We studied its potential role in the internalization and degradation of CSF-1 and its receptor in two primary populations of murine macrophages, namely bone marrow-derived macrophages (BMM) and resident peritoneal macrophages (RPM). Even though CSF-1 induced PI 3-kinase activity in both BMM and RPM, wortmannin, a potent inhibitor of PI 3-kinase activity, at concentrations that inhibited PI 3-kinase activity by 90% in these cells, had little or no effect on receptor internalization and degradation in either BMM or RPM or on CSF-1 degradation by BMM. Strong (more than 90%) inhibition was, however, observed for CSF-1 degradation by RPM. These findings suggest that both wortmannin-sensitive and wortmannin-insensitive pathways of ligand degradation exist in macrophages and that, although CSF-1 and CSF-1 receptor share the same endocytic pathway initially, they might be targeted to different compartments at later stages of degradation.
authors.affiliation: University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
authors.forename: V
authors.initials: V
authors.lastname: Kanagasundaram
authors.forename: E
authors.initials: E
authors.lastname: Christy
authors.forename: J A
authors.initials: JA
authors.lastname: Hamilton
authors.forename: A
authors.initials: A
authors.lastname: Jaworowski
mesh_terms: D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D002451:Cell Compartmentation; D002867:Chromones / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D046911:Macromolecular Substances; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000502:physiology; D051379:Mice; D008808:Mice, Inbred CBA; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D000077191:Wortmannin